Over the years, several methods of administering biologically-effective materials to mammals have been proposed. Many medicinal agents are available as water-soluble salts and can be included in pharmaceutical formulations relatively easily. Problems arise when the desired medicinal agent is either insoluble in aqueous fluids or is rapidly degraded in vivo. Simply by way of example, many of these biologically-effective materials have mercapto-functional groups. These include e.g., antiproliferative and/or immunosuppressive agents such as the mercaptopurines, as well as peptides and proteins with demonstrated or potential utility as medicinal agents. These types of materials often present complex problems of pharmacokinetics and bioavailability based on their poor solubility in blood or tissue fluids, tissue distribution, clearance rate and antigenicity, after administration to an animal in need of such treatment.
For instance, the class of compounds known as nucleoside and nucleotide analogs are potentially useful therapeutically in the treatment of cancers and in immuno-supression, because they interfere with DNA synthesis. This property is useful in treating a broad class of diseases or disorders characterized by excessive or inappropriate cell division. However, the artisan will appreciate that these compounds have a very narrow therapeutic index, requiring careful control of dose, kinetics and tissue concentrations. Thus, there is a need to provide improved nucleoside and nucleotide analogs where more targeted delivery to selected tissues, and/or improved release kinetics is desirable.
For example, 6-mercaptopurine or 6-MP, while otherwise a promising anticancer agent and immunosuppressive, has substantial drawbacks. Absorption of 6-MP is incomplete after oral ingestion and bioavailability is reduced by first-pass metabolism through the liver. It is reported that oral bioavailability of 6-MP is only 5% to 37%, with great variability between patients.
One way to solubilize biologically-effective materials and improve solubility, bioavailability, etc., is to include them as part of a soluble prodrug. Prodrugs include chemical derivatives of a medicinal agent, e.g., a biologically-effective parent compound which, upon administration, eventually liberates the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent, in vivo and can modify the transportation, distribution or solubility of a drug in the body. Furthermore, prodrug formulations often reduce the toxicity and/or otherwise overcome difficulties encountered when administering pharmaceutical preparations. Typical examples of prodrugs include organic phosphates or esters of alcohols or thioalcohols.
Prodrugs are often biologically inert or substantially inactive forms of the parent or active compound. The rate of release of the active drug, typically by hydrolysis, is influenced by several factors, but especially by the type of bond joining the parent drug to the modifier. Care must be taken to avoid preparing prodrugs which are eliminated through the kidney or reticular endothelial system, etc., before a sufficient amount of hydrolysis of the parent compound occurs.
Previous efforts to improve the utility of certain therapeutically useful mercaptan compounds have been reported. For example, azathioprine (IMURAN) is a prodrug of 6-mercaptopurine containing an imidazole group attached to the sulfur at the 6-position of the purine ring. This substitution serves to decrease the rate of inactivation by enzymatic S-methylation, nonenzymatic oxidation, and/or conversion to thiourate by xanthine oxidase. Azathioprine reacts with sulfhydryl compounds such as glutathione (reported to be by nonenzymatic pathways) which produces a more controlled liberation of mercaptopurine in tissues. Azathioprine is also reported to provide enhanced immunosuppressive activity relative to unmodified 6-MP. In spite of this advance, further improvements have been sought in order to deliver various mercaptan-based therapeutic agents in ways which would be therapeutically superior to that which is currently available. For example, it would be desirable to reduce the number of dosages a patient would require and/or more predictable control the rate of release of the drug from a carrier.
Incorporating a polymer as part of a prodrug system has been suggested to increase the circulating life of some drugs having an available hydroxyl or amine group. See, for example U.S. Pat. No. 6,180,095, the contents of which are incorporated herein by reference. The '095 patent discloses polymer-based double prodrug systems using a benzyl elimination (BE) system for controllably delivering biologically active materials in vivo.
While a number of polymeric prodrug systems are known to the art, including those prepared by linking a polyethylene glycol (PEG) to a drug or other agent of interest, conjugates that directly exploit the thiol function groups of many potentially useful biologically effective substances are not believed to be mentioned. Protected sulfur-linked polyethylene glycols are also known, although these ultimately form polymer-drug conjugates via covalent disulfide bonds (—S—S— bonds) not via covalent thiol bonds (—SH— bonds). See Woghiren et al., 1993, Bioconjugate Chem. 4: 314-318, who linked a 5 kDa PEG to papain enzyme by disulfide linkers.
Thus, there remains a need for improved polymeric prodrug systems for thiol- or mercaptan containing compounds. There is also a need for including benzyl elimination systems as part of such prodrug systems. The present invention addresses these needs.